IL-33 Dependent Type 2 Inflammation during Rhinovirus-induced Asthma Exacerbations In Vivo

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1 IL-33 Dependent Type 2 Inflammation during Rhinovirus-induced Asthma Exacerbations In Vivo David J. Jackson, Heidi Makrinioti1, Batika M. J. Rana, Betty W. H. Shamji, Maria-Belen Trujillo-Torralbo, Joseph Footitt, Jerico del-rosario, Aurica G. Telcian, Alexandra Nikonova, Jie Zhu, Julia Aniscenko,Leila Gogsadze, Eteri Bakhsoliani, Stephanie Traub, Jaideep Dhariwal, James Porter, Duncan Hunt,Toby Hunt, Trevor Hunt, Luminita A. Stanciu, Musa Khaitov, Nathan W. Bartlett, Michael R. Edwards,Onn Min Kon, Patrick Mallia, Nikolaos G. Papadopoulos, Cezmi A. Akdis, John Westwick, Matthew J. Edwards, David J. Cousins, Ross P. Walton, and Sebastian L. Johnston Am J Respir Crit Care Med Dec 15;190(12): Journal club Current Topics in Applied Immunology Nazanin Najafi

2 Introduction Rhinoviruses have single-stranded positive sense RNA genomes Rhinovirus infections are The most common trigger for asthma exacerbations The predominant cause of the common cold IL-33 is an epithelial cell derived cytokine, and its receptor (ST2) is expressed on both Th2 cells and ILC2s (Type 2 Innate Lymphoid Cells) IL-33 potently drives production of T helper-2 (Th2)-associated cytokines (IL 4, IL 5, IL 13) IL-33 is expressed on a wide variety of cell types: fibroblasts, mast cells, dendritic cells, macrophages, osteoblasts, endothelial cells, and epithelial cells

3 Available Knowledge Immune responses to viral infections --> CD4 + IFN-δ producing Th1 cells, regarded as the archetypal effector cell of antiviral immunity. In contrast Th2 cells, which secrete IL-4, IL-5, and IL-13, are regarded as critical effector cells in allergic asthma.

4 Objective Does rhinovirus induce a type 2 inflammatory response in asthma in vivo? Does IL-33 have a role in this pathway?

5 Study Design Study volunteers: (n=46) Asthma patients: (n=32) nonsmoking with mild or moderately severe asthma Healthy individuals: (n=14) nonsmoking, nonatopic Age: years NO recent viral illness or serum neutralizing antibodies to rhinovirus 16 (RV16) at screening.

6 Patients with Asthma: Rhinovirus-induced Respiratory Morbidity FEV1: Forced Expiratory Volume in 1 Second PEF: Peak expiratory flow

7 Patients with Asthma: Viral Load than Healthy Subjects Patients with Asthma: Virus-induced Lower Airway Eosinophilia this is the first time a significant rhinovirus-induced eosinophilia has been demonstrated in asthma.

8 Rhinovirus infection in asthma: induction of IL-33 and type 2 cytokines in vivo significant correlations between bronchial IL-33 and both IL-5 and IL-13 in Asthma subjects

9 Type 2 Cytokines and IL-33 Correlate with Clinical Outcomes and Viral Load In asthma, IL-5 and IL-13 levels during infection both positively correlates with respiratory symptom severity The IL-33 level correlates with viral load => respiratory epithelium being both the site of infection and the source of IL-33.

10 Rhinovirus Infection of Primary Human BECs Ex Vivo Rhinovirus infection of the bronchial epithelium leads to the release of large amounts of IL-33 Functional role of IL-33 in inducing Th2 responses activated, nonpolarized human CD4 + T cells (Th0 cells) were cultured with media alone and with supernatants from rhinovirus infected or uninfected BECs. The Th0 cells cultured with supernatants from rhinovirus-infected BECs had significantly higher frequencies of IL-4 +, IL-5 +, IL-13 + cells

11 Rhinovirus Infection of Primary Human BECs Ex Vivo Functional role of IL-33 in inducing Th2 responses GATA3 transcription factor Promotes secretion of IL-4, 5,13 Induces differentiation of Th0 cells to Th2 Supresses differentiation to Th1 induction of Th2 responses was dependent on IL-33, as it was completely inhibited by pretreatment of the Th0 cells with anti-st2 monoclonal antibody

12 Rhinovirus Infection of Primary Human BECs Ex Vivo IL-33 activates human ILC2s to produce type 2 cytokines Critically, IL-5 and IL-13 induction was again completely blocked by anti-st2 treatment IL-33 is the key factor in this pathway Rhinovirus trigger of IL-33 is therefore likely to drive an early and robust type 2 response via these innate cells.

13 Summary Patients with Asthma Experience Greater Rhinovirus-induced Respiratory Morbidity and Viral Load than Healthy Subjects Virus-induced Lower Airway Eosinophilia is increased in Asthma IL-33 Is Induced by Rhinovirus infection In Vivo and is Related to Type 2 Responses Type 2 Cytokines and IL-33 Correlate with Clinical Outcomes and Viral Load IL-33 Present in Rhinovirus-infected BEC Supernatants Induces Th2 responses in human T Cells Induces IL-5 and IL-13 production by human ILC2s

14 Conclusion Virus-induced IL-33 and IL-33 responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations. IL-5 Esosinophilic inflammation IL-33 IL-13 Airway remodelling IL-4 IgE Class switching

15 Thank you for your attention